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Cell Metabolism Nov 2021As tissue macrophages of the central nervous system (CNS), microglia constitute the pivotal immune cells of this organ. Microglial features are strongly dependent on...
As tissue macrophages of the central nervous system (CNS), microglia constitute the pivotal immune cells of this organ. Microglial features are strongly dependent on environmental cues such as commensal microbiota. Gut bacteria are known to continuously modulate microglia maturation and function by the production of short-chain fatty acids (SCFAs). However, the precise mechanism of this crosstalk is unknown. Here we determined that the immature phenotype of microglia from germ-free (GF) mice is epigenetically imprinted by H3K4me3 and H3K9ac on metabolic genes associated with substantial functional alterations including increased mitochondrial mass and specific respiratory chain dysfunctions. We identified acetate as the essential microbiome-derived SCFA driving microglia maturation and regulating the homeostatic metabolic state, and further showed that it is able to modulate microglial phagocytosis and disease progression during neurodegeneration. These findings indicate that acetate is an essential bacteria-derived molecule driving metabolic pathways and functions of microglia during health and perturbation.
Topics: Acetates; Animals; Brain; Fatty Acids, Volatile; Immune System; Mice; Microbiota
PubMed: 34731656
DOI: 10.1016/j.cmet.2021.10.010 -
Nature Cancer Oct 2023Acetate metabolism is an important metabolic pathway in many cancers and is controlled by acetyl-CoA synthetase 2 (ACSS2), an enzyme that catalyzes the conversion of...
Acetate metabolism is an important metabolic pathway in many cancers and is controlled by acetyl-CoA synthetase 2 (ACSS2), an enzyme that catalyzes the conversion of acetate to acetyl-CoA. While the metabolic role of ACSS2 in cancer is well described, the consequences of blocking tumor acetate metabolism on the tumor microenvironment and antitumor immunity are unknown. We demonstrate that blocking ACSS2, switches cancer cells from acetate consumers to producers of acetate thereby freeing acetate for tumor-infiltrating lymphocytes to use as a fuel source. We show that acetate supplementation metabolically bolsters T-cell effector functions and proliferation. Targeting ACSS2 with CRISPR-Cas9 guides or a small-molecule inhibitor promotes an antitumor immune response and enhances the efficacy of chemotherapy in preclinical breast cancer models. We propose a paradigm for targeting acetate metabolism in cancer in which inhibition of ACSS2 dually acts to impair tumor cell metabolism and potentiate antitumor immunity.
Topics: Humans; Female; Breast Neoplasms; Acetyl Coenzyme A; Cell Line, Tumor; Acetates; T-Lymphocytes; Immunologic Factors; Tumor Microenvironment
PubMed: 37723305
DOI: 10.1038/s43018-023-00636-6 -
Microbiome Jun 2021Modification of the gut microbiota has been reported to reduce the incidence of type 1 diabetes mellitus (T1D). We hypothesized that the gut microbiota shifts might also...
BACKGROUND
Modification of the gut microbiota has been reported to reduce the incidence of type 1 diabetes mellitus (T1D). We hypothesized that the gut microbiota shifts might also have an effect on cognitive functions in T1D. Herein we used a non-absorbable antibiotic vancomycin to modify the gut microbiota in streptozotocin (STZ)-induced T1D mice and studied the impact of microbial changes on cognitive performances in T1D mice and its potential gut-brain neural mechanism.
RESULTS
We found that vancomycin exposure disrupted the gut microbiome, altered host metabolic phenotypes, and facilitated cognitive impairment in T1D mice. Long-term acetate deficiency due to depletion of acetate-producing bacteria resulted in the reduction of synaptophysin (SYP) in the hippocampus as well as learning and memory impairments. Exogenous acetate supplement or fecal microbiota transplant recovered hippocampal SYP level in vancomycin-treated T1D mice, and this effect was attenuated by vagal inhibition or vagotomy.
CONCLUSIONS
Our results demonstrate the protective role of microbiota metabolite acetate in cognitive functions and suggest long-term acetate deficiency as a risk factor of cognitive decline. Video Abstract.
Topics: Acetates; Animals; Bacteria; Brain; Cognitive Dysfunction; Diabetes Mellitus, Experimental; Gastrointestinal Microbiome; Mice
PubMed: 34172092
DOI: 10.1186/s40168-021-01088-9 -
American Journal of Health-system... Jan 2022
Topics: Acetates; Humans; Piperidines
PubMed: 34849553
DOI: 10.1093/ajhp/zxab377 -
International Journal of Toxicology Aug 2024The Expert Panel for Cosmetic Ingredient Safety reviewed newly available studies since their original assessment in 1982 and a previous re-review in 2002, along with... (Review)
Review
The Expert Panel for Cosmetic Ingredient Safety reviewed newly available studies since their original assessment in 1982 and a previous re-review in 2002, along with updated information regarding product types and concentrations of use. Considering this information, the Panel confirmed that Laneth-9 Acetate and Laneth-10 Acetate are safe for topical application to humans in the present practices of use and concentration as described in this report.
Topics: Humans; Cosmetics; Animals; Acetates; Consumer Product Safety
PubMed: 38653732
DOI: 10.1177/10915818241249398 -
Nature Cell Biology Apr 2024The ability of tumour cells to thrive in harsh microenvironments depends on the utilization of nutrients available in the milieu. Here we show that pancreatic...
The ability of tumour cells to thrive in harsh microenvironments depends on the utilization of nutrients available in the milieu. Here we show that pancreatic cancer-associated fibroblasts (CAFs) regulate tumour cell metabolism through the secretion of acetate, which can be blocked by silencing ATP citrate lyase (ACLY) in CAFs. We further show that acetyl-CoA synthetase short-chain family member 2 (ACSS2) channels the exogenous acetate to regulate the dynamic cancer epigenome and transcriptome, thereby facilitating cancer cell survival in an acidic microenvironment. Comparative H3K27ac ChIP-seq and RNA-seq analyses revealed alterations in polyamine homeostasis through regulation of SAT1 gene expression and enrichment of the SP1-responsive signature. We identified acetate/ACSS2-mediated acetylation of SP1 at the lysine 19 residue that increased SP1 protein stability and transcriptional activity. Genetic or pharmacologic inhibition of the ACSS2-SP1-SAT1 axis diminished the tumour burden in mouse models. These results reveal that the metabolic flexibility imparted by the stroma-derived acetate enabled cancer cell survival under acidosis via the ACSS2-SP1-SAT1 axis.
Topics: Animals; Mice; Cancer-Associated Fibroblasts; Cell Line, Tumor; Acetates; Pancreatic Neoplasms; Polyamines; Tumor Microenvironment
PubMed: 38429478
DOI: 10.1038/s41556-024-01372-4 -
American Journal of Health-system... Jan 2024
Topics: Humans; Acetates
PubMed: 37862457
DOI: 10.1093/ajhp/zxad253 -
Cell Metabolism Jul 2023The metabolic mechanisms supporting the process of endothelial-to-mesenchymal transition (EndMT) remain largely unknown. Here, Zhu et al. describe a novel role for...
The metabolic mechanisms supporting the process of endothelial-to-mesenchymal transition (EndMT) remain largely unknown. Here, Zhu et al. describe a novel role for acetate and ACC2 in regulating EndMT and atherosclerosis via modulation of the TGF-β signaling. This study sheds light on the role of glucose-derived metabolites that drive endothelial pathophysiology.
Topics: Humans; Acetates; Atherosclerosis; Glucose; Transforming Growth Factor beta
PubMed: 37437542
DOI: 10.1016/j.cmet.2023.06.006 -
The Journal of Nutrition Nov 2021In the last few years, there has been a growing interest in the role of gut microbiota in the development of obesity and its complications. (Clinical Trial)
Clinical Trial
BACKGROUND
In the last few years, there has been a growing interest in the role of gut microbiota in the development of obesity and its complications.
OBJECTIVES
In this study, we tested the following hypotheses: 1) lean youth and youth with obesity experience a different capability of their gut microbiota to ferment carbohydrates and produce acetate; and 2) colonic acetate may serve as a substrate for hepatic de novo lipogenesis (DNL).
METHODS
Nineteen lean youth [mean ± SE BMI (in kg/m2): 21.8 ± 0.521] and 19 youth with obesity (BMI: 35.7 ± 1.66), ages 15-21 y, frequency-matched by age and sex, underwent a fasting 10-h sodium [d3]-acetate intravenous infusion to determine the rate of appearance of acetate (Raacet) into the peripheral circulation before and after an oral dose of 20 g of lactulose. Pre- and post-lactulose Raacet values were determined at a quasi-steady state and changes between groups were compared using a quantile regression model. Acetate-derived hepatic DNL was measured in 11 subjects (6 youth with obesity) and its association with Raacet was assessed using Spearman correlation.
RESULTS
Mean ± SE Raacet was not different before lactulose ingestion between the 2 groups (7.69 ± 1.02 μmol · kg-1 · min-1 in lean youth and 7.40 ± 1.73 μmol · kg-1 · min-1 in youth with obesity, P = 0.343). The increase in mean ± SE Raacet after lactulose ingestion was greater in lean youth than in youth with obesity (14.7 ± 2.33 μmol · kg-1 · min-1 and 9.29 ± 1.44 μmol · kg-1 · min-1, respectively, P = 0.001). DNL correlated with Raacet, calculated as changes from the pre- to the post-lactulose steady state (ρ = 0.621; P = 0.046).
CONCLUSIONS
These data suggest that youth with obesity ferment lactulose to a lesser degree than youth without obesity and that colonic acetate serves as a substrate for hepatic DNL.This trial was registered at clinicaltrials.gov as NCT03454828.
Topics: Acetates; Adolescent; Colon; Female; Fermentation; Gastrointestinal Microbiome; Humans; Male; Obesity; Young Adult
PubMed: 34494088
DOI: 10.1093/jn/nxab277 -
The New Phytologist Aug 2023While traditionally considered important mainly in hypoxic roots during flooding, upregulation of fermentation pathways in plants has recently been described as an... (Review)
Review
While traditionally considered important mainly in hypoxic roots during flooding, upregulation of fermentation pathways in plants has recently been described as an evolutionarily conserved drought survival strategy, with acetate signaling mediating reprograming of transcription and cellular carbon and energy metabolism from roots to leaves. The amount of acetate produced directly correlates with survival through potential mechanisms including defense gene activation, biosynthesis of primary and secondary metabolites, and aerobic respiration. Here, we review root ethanolic fermentation responses to hypoxia during saturated soil conditions and summarize studies highlighting acetate fermentation under aerobic conditions coupled with respiration during growth and drought responses. Recent work is discussed demonstrating long-distance transport of acetate via the transpiration stream as a respiratory substrate. While maintenance and growth respiration are often modeled separately in terrestrial models, here we propose the concept of 'Defense Respiration' fueled by acetate fermentation in which upregulation of acetate fermentation contributes acetate substrate for alternative energy production via aerobic respiration, biosynthesis of primary and secondary metabolites, and the acetylation of proteins involved in defense gene regulation. Finally, we highlight new frontiers in leaf-atmosphere emission measurements as a potential way to study acetate fermentation responses of individual leaves, branches, ecosystems, and regions.
Topics: Fermentation; Ecosystem; Acetates; Energy Metabolism; Plant Roots
PubMed: 37282715
DOI: 10.1111/nph.19015